1. The Technical Field
The invention relates to a conglomerate of controlled relative density for containing or carrying at least one active substance to be used in a fluid; methods of preparing such a conglomerate; and the use of such a conglomerate as a solid phase matrix, carrier, or substrate material in a fluid bed rector, or in a batch reactor; as a carrier of substances for sustained release; as a food material, medical, and vaccine for fish, or other animals living in water; as a material for treating waste water and polluted waters; and as a material for treating polluted water such as oil polluted sea water.
Further, the invention relates to a method of distributing a fluid in the fluid bed of a fluid bed reactor; and a fluid bed reactor using such a method.
In the present context the expression "conglomerate" is intended to designate a composite of basic particles, which may comprise particles of different types and sizes, held together by conglomerating agents. Conglomerates may be of various sizes, and shapes and should preferably exhibit various degrees of mechanical rigidity depending on the application. Further, conglomerates may be chemically active or may be chemically inactive under the conditions applied.
The expression "conglomerate of controlled relative density" is intended to designate a conglomerate or a conglomerate particle for which in particular the basic particles are chosen in predetermined amounts to provide a certain relative density of the conglomerate with respect to the fluid in which an active substance or another constituent of the conglomerate is to be used so that the floatability or sedimentation, respectively, is controlled. Thus, conglomerates according to the invention are intentionally designed with respect to the density of the medium for their particular purpose of application, including proper consideration of the influence of their sizes on their floating or sedimentation properties. In other media, e.g. during preparation or during storage under e.g. dry conditions, the conglomerate may have a density different from than that in the fluid medium of use, such fluids may be liquids or gases.
In the present context the expression "active substance" should be taken in a very broad sense comprising agents having desired properties for their particular purpose of application, e.g. adsorbents, ligands, reagents, enzymes, catalysts; natural substances and substrates, cell aggregates; or nutritional matter for animals living in water; entrapped in or chemically, e.g. covalently, ionically, photochemically, etc. bound to the conglomerate of controlled density.
Carrier materials for carrying at least one active substance are used in a wide variety of applications in chemical and biological processes, such as production and manufacturing of chemical or pharmaceutical products, e.g. for carrying catalysts in liquid phase oil conversion technology, for carrying enzymes for modifying synthetical products, e.g. enzymes such as proteases, invertases, amidases and ring forming enzymes for synthesis of lactones, and carboxypeptidase for synthesis of peptides using solid-phase techniques; fermentation and cell growth, e.g. for carrying cells or substrate; waste water purification, e.g. for carrying enzymes and/or microorganisms, catalysts or adsorbents; chromatographic processes, e.g. high performance liquid chromatography, gel filtration, ion exchange and affinity chromatography, e.g. for carrying adsorbents; diagnostic processes, e.g. for carrying adsorbents for blood purification, dyechromatographic processes for albumine purification; and prophylactic processes, e.g. for carrying immobilized antibodies or antigens in extracorporael circulations for removal of antigens or antibodies, bacterial toxins or other toxins, and autoimmune diseases.
2. Prior Art Disclosure
There are numerous disclosures in the prior art concerning particles prepared from organic and inorganic materials. However, carriers comprising conglomerates of controlled relative density with respect to the fluid of use carrying or for carrying at least one active substance have apparently never been disclosed.
Kuraray Co., Ltd., C.A. 98:157436t discloses beads, particles, fibres, sheets, and tubes of glass, activated carbon, silica, alumina or high molecular weight substances coated with copolymers of acrylates and carboxylic acids or amines to form selective adsorbent carriers or supports for use in selective electrodes or in column chromatography.
Sakuma et al., C.A. 111:74363c, disclose glass or polymer spheres coated with hydroxyapatite for use as a stationary phase for column chromatography.
EP-A-0266580 discloses a method for coating solid particles with a hydrophilic gel preferably agarose for various separating processes in packed columns based on adsorbent groups, e.g. ion exchanging groups, hydrophobic groups, or groups with biospecificity chemically bound to a gel. Such coating may be provided by mixing hydrophilic solid particles with a gel-forming substance above the gelling temperature in which each individual particle is coated, separated from each other, and cooled below the gelling temperature, essentially to stabilize the particles against the high pressure in e.g. HPLC applications.
Generally, all of the above mentioned coated particles are provided by coating individual particles made of the same material and having the same density.
U.S. Pat. No. 4,698,317 discloses hollow microspherical glass particles having open pores, and being prepared by spray thermal decomposition of a solution, in an aqueous organic solvent, wherein the water content promotes open pore formation.
U.S. Pat. No. 2,797,201 discloses substantially spherical, hollow particles having a "thin, strong skin" being prepared by thermal treatment of droplets of a solution of a film forming material, e.g. an organic polymer such as a phenolformaldehyde resin, and optionally further containing a "blowing agent", i.e an agent generating gas at the elevated temperature of the thermal treatment.
GB 2151601B discloses porous hollow particles of an inorganic material and a composite material comprising such particles supporting a selected substance such as a chromatographic organic gel. The porous hollow particles may be formed by coating a fugitive core material, e.g. organic resin beads or alginate spheres, with inorganic material, and then heating to remove the fugitive core material. Further, GB 2151602B discloses closely similar particles wherein a magnetic material, such as ferric oxide, nickel oxid or cobalt oxide, is incorporated in the inorganic shell of the particle.
The 3M Corporation (USA) markets a number of types of substantially impermeable, hollow micro-spheres of silicious material. For example synthetically manufactured soda-lime borosilicate glass micro-spheres marketed by 3M in a variety of size fractions. Also, permeable hollow spheres of siliceous material derived from fly-ash are provided by Fillite Ltd., Runcorn, England. However, none of the commercially available micro-spheres are conglomerates of controlled relative density according to the invention.
EP-A-0021563 discloses a material suitable for thermosetting which includes a collection of hollow particles adhesively mixed with a thermosetting resin and which material may be converted by thermosetting in to a fused solid mass having a density not greater than 0.5 g/cm.sup.3.
GB-A-2196252 discloses an oral, solid, pharmaceutical dosage form comprising conventional matrix binders including starch and cellulose, or their derivatives, and a pharmaceutically acceptable weighting agent, including inorganic compounds such as salts, oxides, or hydroxides of a metal, e.g. barium sulphate or ferrous oxide, suitable for oral administration to humans and for controlled release of a pharmaceutically active ingredient into the stomach. The controlled release unit may have any chosen density from about 2 g/ml to about 6 g/ml and may in case of a conventional pellet have a size from about 1 to about 1.4 mm, and in case of a tablet a size above 10 mm. Nothing is disclosed nor suggested about non-solid i.e. permeable or porous conglomerates of controlled relative density according to the invention. Furthermore, the described pharmaceutical dosage form consists of solid particles comprising a binder and a weighting agent soluble in gastic fluid which makes the pellet or tablet disintegrate shortly after ingestion.
Generally, for a large number of applications, the active substance to be used in a fluid may only temporarily be available or accessible at the right places in the fluid. Thus, for inert carrier particles carrying active substances and often showing large variations in dispersion properties, e.g. sedimention or floatation, the active substances may be carried in an uncontrolled manner e.g. down- or upwards in relation to the fluid depending on the relative density of the carrier.
In fluid bed reactors partially solving the problems of packed bed columns, i.e the problems of suspended matter clogging up the solid-phase bed which increases the back pressures and compresses the bed disturbing the flow through the bed, the carrier particles are carrying the active substance in a free, fluid phase by applying a flow having an opposite direction to the direction of the relative movement of the carrier. Thus, carrier particles having a density larger than the fluid and moving downwards due to gravity may be kept in a free, fluid phase by an upwards flow of fluid. Also, carrier particles having a density less than the fluid and thus moving upwards may due to buoyancy be kept free, fluid phase by a downwards flow of fluid.
For fluid bed solid-phase chemical processes, the density of the solid-phase carrier particle is very important in controlling bed properties. However, up to now, the design of solid-phase carrier particles has been limited by the available material.
Generally, particles may either be designed to be impermeable to the fluid, in which case the available surface area per unit volume is small; or particles may be designed to be permeable to the fluid, in which case the material chosen has to have the correct density per se. Unfortunately, the most interesting materials for many applications, e.g. materials such as natural and synthetic polysaccharides like agar, alginates, carrageenans, agarose, dextran, modified starches, and celluloses; synthetic organic polymers and copolymers typically based on acrylic monomers used for chromatographic purification of proteins in packed bed columns are not of suitable density per se. Therefore, these materials are difficult to apply in fluid bed reactors.
However, certain types of organic polymers and certain types of silica based materials may be produced to provide carrier particles of suitable density, but such carriers may not at the same time be suitable active substances, e.g. for protein purification procedures, where such materials may provide low permeability, non-specific interactions and denature bound proteins. Further, for such polymers, it may be difficult and expensive to design derivatisation schemes for affinity chromatography media. Also, certain types of permeable silica particles have been used for fluid bed applications. However, the properties of these materials are far from optimal. Thus, the materials are instable at pH above 7, fragile to shear forces, and provide non-specific interactions.
U.S. Pat. No. 4,032,407 discloses a tapered bed bioreactor applying immobilized biological catalysts or enzymatic systems on fluidizable particulate support materials consisting of coal, alumina, sand, and glass, i.e. materials heavier than the fluid.
EP-A-0175568 discloses a three phase fluidized bed bioreactor process comprising purifying effluents in a three phase fluidized bed comprising solid particles being made by mixing a binder with an inorganic materiel based on aluminum silicate, granulating the resulting mixture, and firing the granules to sinter them. The specific gravity of the sintered granules is adjusted to fall into a specific range from 1.2 to 2.0 by varying the mixing ratio of inorganic powdery materials based on aluminum and binders, said sintered granules having a diameter from 0.1 to 5 mm.
EP-A-0025309 discloses a downflow fluid bed bioreactor applying biota attached to carrier particles consisting of cork, wood, plastic particles, hollow glass beads or other light weight material and having a specific gravity which is less than that of a liquid sprayed onto the upper part of a fluid bed of suspended carrier particles and conducted downward through the bed.
These three disclosures describe particulate support materials to which the attachment of the active substance is restricted to the surface of the particles limiting the amount of active substance to be obtained per unit volume compared to particles allowing the active substance to be attached within the particle. Thus, in many applications, it is important to have specifically designed particles able to carry as large an amount of active substance per unit volume as possible which particles are not available in the prior art.
Thus, in great many applications of active substances in fluids, there is a need for materials of controlled relative density carrying or for carrying active substances in the fluids.
Further, a disadvantage is that the fluid is distributed in the fluid bed of a fluid bed reactor by spraying whereby channels are formed in the bed by the impinging fluid rays.
International Application Publication No. WO81/02844 discloses a multi-lagered filter medium comprising particles formed of hollow silica beads distributed in a matrix of cured cement having a uniform specific gravity in the range from 1.02 to about 1.5; said particles being adapted for use as sucessive layers in a deep bed filter to promote agitation and scrubbing of the particles and to separate the particles more efficiently during backwash, i.e. for a use which does not involve an active substance. The particles are prepared by casting a slurry of hollow silica beads dispersed in a binder material such as cement; curing the casted slurry to a self-sustaining state; and cutting the cured casted slurry into polygonal granules; said granules then being completely cured. Nothing is indicated or suggested about using an organic binder material, and providing the granules with an active substance.
EP-A-0005650 discloses an up-flow fluid bed reactor having fluidizing fluid flow distributors at the bottom thereof providing flow paths to avoid turbulens effects. Besides requiring complicated flow paths, a disadvantage of such a distributor is that it may be clogged by particulate matter.
U.S. Pat. No. 4,142,969 discloses an oleospecific hydrophobic composition comprising an intimate mixture of expanded volcanic glass consisting of perlite, a cellulose fiber, and a water repellent sizing consisting of asphalt; and a method of sorbing oleaginous compounds e.g. in selectively removing oil from the surface of water. The constituents are incorporated into a homogeneous product by a wet process, dried in an oven until essentially all moisture has been removed, and then ground up into a fluffy low density material. Nothing is disclosed nor suggeted about controlling the density of the composition by incorporation of high or low density particles.